The association between Interleukin (IL)-4 gene intron 3 VNTR polymorphism and alopecia areata (AA) in Turkish population
Introduction
Alopecia areata (AA) is a common and genetically complex hair loss disorder that affects approximately 1–2% of the general population. AA affects both sexes and all age groups (Safavi et al., 1995). Oval patches of non-scarring hair loss which has a sudden onset and recurrent course forms are the most familiar clinical appearance of AA (Martinez-Mir et al., 2007). The exact aetiopathogenesis of AA remains unknown. However, AA is thought to be a tissue-specific autoimmune disease directed against the hair follicle causing the patient to develop antibodies to their own hair follicle structures and suppressing or stopping hair growth (Tobin, 2003). The strong association between AA and autoimmune diseases supports this idea (Garg and Messenger, 2009). AA hair follicles are surrounded by an immune infiltrate with activated T-helper cells (Th cells), cytotoxic T cells (TC cells) and natural killer (NK) cells, characterized as a Th1-type inflammatory response (Gilhar et al., 1999, Gilhar et al., 2003). Approximately 20% of affected people have a positive family history of the disease, suggesting a genetic predisposition. Hence, AA can be considered a genetically determined immune-mediated disorder (Garg and Messenger, 2009).
Interleukin-4 (IL-4) is a key cytokine secreted by Th2 lymphocytes, eosinophils and mast cells (Rocken et al., 1996) and induces the activation and differentiation of B cells and the development of the Th2 subset of lymphocytes. It has cytotoxic, anti-tumor and numerous anti-inflammatory effects (Sobti et al., 2010). The biological actions of IL-4 include stimulation of IgE and mast cell eosinophil-mediated reactions. IL-4 is the principal cytokine that stimulates B-cell immunoglobulin heavy-chain switching to the IgE isotype (Del Prete et al., 1988). It has been demonstrated that an imbalance between Th1 and Th2 cytokine production is highly correlated with the induction and development of several autoimmune diseases (Kidd, 2003).
Although there are increased levels of Th1 cytokines, Th2 immune response is also implicated in the pathogenesis of AA (Katagiri et al., 2007, Teraki et al., 1996). The role of IL-4 levels in alopecia areata patients has not been clarified yet with the controversial results taken from different studies; in some studies, it is elevated but in the others, it has decreased levels (Alzolibani et al., 2012, Attia et al., 2010, Katagiri et al., 2007, Nakamura et al., 2008; Teraki et al., 1996).
Genetic polymorphisms in cytokine genes affect gene transcription and cause inter-individual variations in cytokine production, thus influencing the outcome of infectious diseases, cancers, and autoimmune diseases (Alzolibani et al., 2012). Because of its key position in IgE production and in the induction of inflammation, IL-4 is an attractive gene thereby contributing towards autoimmunity. Polymorphisms in the IL-4 gene may change the levels of the cytokine and cause disturbance in immune functioning, and have role in several autoimmune diseases. Genetic variants of the promoter region of IL-4 have been related to elevated levels of serum IgE (Galbraith and Pandey, 1995).
There are numerous polymorphisms associated with AA. Among these, tumor necrosis factors alpha (TNFa) and beta (TNFb) have been extensively analyzed. Polymorphisms in TNFa gene have shown to be strongly associated with autoimmune/inflammatory pathologies, just like IL-4 VNTR polymorphism (Galbraith and Pandey, 1995, Schueller et al., 2006). However there is no report about the relationship of IL-4 gene intron 3 VNTR polymorphism and AA up to now. As immunological and genetic factors have been implicated in the pathogenesis of AA, the purpose of the present study was to investigate possible associations between the functional IL-4 VNTR polymorphism and AA susceptibility and disease progression in Turkish population.
Section snippets
Subjects
The study group consisted of 116 unrelated patients with AA (67 males and 49 females; mean age: 32.54 ± 9.679 standard deviation [SD] years), and 125 (63 males and 62 females; mean age: 30.06 ± 11.319 SD years) unrelated healthy controls with no scalp lesions in their personal history or on clinical examination. AA patients were gathered from Department of Dermatology of Gaziosmanpasa University, Tokat, Turkey. Clinical data were obtained from all patients, including about their demographics,
Results
The baseline clinical and demographical features of the study patients with AA were shown in Table 1. Gender, age, disease duration, number of attacks, family history, emotional stress, focal infection, nail dystrophy, alopecia severity and alopecia localization of AA patients were analyzed. Age and gender were not different between patient and control groups. The three genotypes of intron 3 VNTR polymorphism of IL-4 gene were classified as: P1P1 (183 bp–two 70 bp repeat allele), P2P2 (253
Discussion
In this study, we investigated the association of VNTR polymorphism in the IL-4 gene with the diagnosis of AA in a group of Turkish patients to establish whether it is a risk factor or not for the development of AA. We determined statistically significant association between intron 3 VNTR polymorphism of IL-4 gene and AA susceptibility in Turkish population. To our knowledge, no previous studies have been carried out to determine the association of VNTR polymorphism in the IL-4 gene and AA in
Conclusion
In conclusion, our results strongly suggest that IL-4 gene VNTR polymorphism in the intron 3 region may be a risk factor for the development of AA among Turkish population. These results contribute to the genetic basis for AA development. Additional studies with larger populations will be necessitated in order to better illuminate the immunopathogenesis of AA.
References (37)
- et al.
Alopecia areata is a T-lymphocyte mediated autoimmune disease: lesional human T-lymphocytes transfer alopecia areata to human skin grafts on SCID mice
J. Invest. Dermatol. Symp. Proc.
(1999) Transfer of alopecia areata in the human scalp graft/Prkdc(scid) (SCID) mouse system is characterized by a TH1 response
Clin. Immunol.
(2003)- et al.
Alopecia areata: autoimmunity the evidence is compelling
J. Investig. Dermatol. Symp. Proc.
(2003) A population-based study of IL4 polymorphisms in multiple sclerosis
J. Neuroimmunol.
(2003)Genomewide scan for linkage reveals evidence of several susceptibility loci for alopecia areata
Am. J. Hum. Genet.
(2007)- et al.
Controlled delivery of T box21 small interfering RNA ameliorates autoimmune alopecia (Alopecia Areata) in aC3H/HeJ mouse model
Am. J. Pathol.
(2008) Alopecia areata investigational assessment guidelines — Part II. National Alopecia Areata Foundation
J. Am. Acad. Dermatol.
(2004)- et al.
IL-4-induced immune deviation as antigen-specific therapy for inflammatory autoimmune disease
Immunol. Today
(1996) - et al.
Incidence of alopecia areata in Olmsted County, Minnesota, 1975 through 1989
Mayo Clin. Proc.
(1995) Biphasic response against aeroallergen in atopic dermatitis showing a switch from an initial TH2 response to a TH1 response in situ: an immunocytochemical study
Allergy Clin. Immunol.
(1996)
Characterization of hair follicle antigens targeted by the anti-hair follicle immune response
J. Investig. Dermatol. Symp. Proc.
Occurrence and clinical relevance of an interleukin-4 gene polymorphism in patients with multiple sclerosis
J. Neuroimmunol.
Epidemiologic and genetic characteristics of alopecia areata (part 1)
Acta Dermatovenerol. Alp. Panonica Adriat.
Epidemiologic and genetic characteristics of alopecia areata (part 2)
Acta Dermatovenerol. Alp. Panonica Adriat.
Serum interleukin-4 and total immunoglobulin E in nonatopic alopecia areata patients and HLA-DRB1 typing
Dermatol. Res. Pract.
Molecular mechanisms of IgE regulation
J. Allergy Clin. Immunol.
Association of IL-4 and IL-1RN (receptor antagonist) gene variants and the risk of type 2 diabetes mellitus: a study in the North Indian population
Ind. J. Med. Sci.
IL-4 is an essential factor for the IgE synthesis induced in vitro by human T cell clones and their supernatants
J. Immunol.
Cited by (36)
The current state of knowledge of the immune ecosystem in alopecia areata
2022, Autoimmunity ReviewsCitation Excerpt :Numerous studies of various methodologies examining gene relationships with AA have been conducted. Many of the earlier studies used focused or targeted techniques to identify associations with specific loci or genes (Table 1) [12–21]. Genome wide assessments have more recently been used to perform more comprehensive and unbiased analyses of susceptible genes in AA patients.
Evaluation of the level of serum Interleukins (IL-2, IL-4, IL-15 andIL-17) and its relationship with disease severity in patients with alopecia areata
2021, Anais Brasileiros de DermatologiaFull scalp hair regrowth in a 4-year-old girl with alopecia areata and atopic dermatitis treated with dupilumab
2020, JAAD Case ReportsCitation Excerpt :The patient's scalp hair has fully regrown without the use of additional therapy. AA is strongly associated with atopic diatheses,4 and polymorphisms in interleukin 4 (IL-4) and IL-13 have been described in patients with AA.5,6 The pathogenesis of AA remains to be elucidated.
Multiple morphological abnormalities of the sperm flagella (MMAF)-associated genes: The relationships between genetic variation and litter size in goats
2020, GeneCitation Excerpt :The QRICH2-P4, CFAP43-P20, and CFAP69-P7 indels did not show strong LD with each other (r2<0.33) (Fig. 3). Previous studies have reported that polymorphisms within candidate genes have positive effects on gene expression in livestock and thus lead to improvements in various economically important traits (Kalkan et al., 2013; Kanzi et al., 2016; Vaz-Drago et al., 2017). For example, a nucleotide substitution in intron 3 of porcine IGF2 gene was found to be associated with a significant increase in skeletal muscle; these effects were mediated by a transcription factor called ZBED6 (Van Laere et al., 2003; Xiang et al., 2018).
Alopecia Areata Is Associated with Atopic Diathesis: Results from a Population-Based Study of 51,561 Patients
2020, Journal of Allergy and Clinical Immunology: In PracticeCitation Excerpt :Increasing evidence for a possible role of TH2 immune pathway in AA is supported by the high levels of TH2-related cytokines (eg, IL-4, IL-5, and IL-10) in the skin and serum of patients with AA as well as findings of eosinophilia and elevated IgE levels in their blood.17,19-21 Moreover, genetic studies have identified polymorphisms in filaggrin, IL-4, and IL-13 (key players of the TH2 pathway) in patients with AA, and associated filaggrin mutations with AA severity.19,22,23 Few preliminary epidemiological studies and meta-analyses have shown a higher prevalence of atopic diseases, such as atopic dermatitis (AD), asthma, and allergic rhinitis (commonly driven by TH2 skewing) in patients with AA, hinting toward a shared immunological background in these conditions.3,24-28
Cytokine Targeted Therapeutics for Alopecia Areata: Lessons from Atopic Dermatitis and Other Inflammatory Skin Diseases
2018, Journal of Investigative Dermatology Symposium Proceedings